ABSTRACT Cavitation induced by ultrasound combined with systemically administered ultrasound contrast agents (UCAs) has been extensively studied over the past decade, and successfully applied to the delivery of a number of different drugs to solid tumours. A limitation of this approach is that the UCAs are confined to blood vessels and the perivascular space, which limits their access to poorly vascularized regions of a tumor. Increased interstitial pressure, high tumor cell density, and stromal barriers further inhibit drug delivery. Inducing de novo cavitation throughout tumor tissue using pulsed focused ultrasound (pFUS) would thus be very beneficial for overcoming these barriers to drug penetration. However, according to current consensus in the field, the focal pressure levels required to nucleate and sustain inertial cavitation are substantially higher than for UCA-enhanced ultrasound and can only be achieved with high-power, highly focused transducers with a large footprints. This limits the practicality of this approach. Our preliminary data indicate that the inertial cavitation activity that results in tissue permeabilization can be achieved at lower peak negative pressures if a shock front develops in the focal waveform, due to nonlinear propagation effects. Further, we have demonstrated that the relationship between the shock amplitude and peak negative pressure is primarily determined by the F-number of a FUS transducer, with less focused transducers producing shocks at the lowest peak negative pressure values. We also showed that shocked waveforms can be achieved using diagnostic ultrasound probes at relatively low mechanical index (MI ~ 4-6) at relevant depth in attenuative tissue. The overall goal of this proposal is to develop feedback controlled pFUS treatment protocols for drug delivery to solid tumours that can be implemented using small footprint, (potentially diagnostic) ultrasound probes. Such permeabilization procedures could be performed just prior to the administration of chemotherapy on any tumor that can be imaged with ultrasound. To achieve our goal, we propose to determine the dependence of the focal waveform metrics and associated cavitation activity on the shape and frequency of the transducer through numerical modelling and a series of experiments in transparent tissue-mimicking gel phantoms and ex vivo tissues (Specific Aims 1 and 2 correspondingly). Direct observation of bubble dynamics using high-speed photography in transparent gels will be correlated with active and passive cavitation detection observations for use in subsequent experiments in tissue. The optimized pFUS treatment protocols will then be applied to healthy porcine tissues (liver, kidney and pancreas), and to subcutaneous Dunning rat prostatic adenocarcinoma, and will be followed by systemic administration of fluorescent labelled dextrans of different molecular weights (Specific Aim 3). The permeabilization effect will be evaluated acutely from the absolute concentration and distribution of the dextrans in tissue. The durability of pFUS-induced permeabilization will be evaluated in a short survival study in rats, by varying the time interval pFUS application and dye administration.